Bleeding with vascular endothelial growth factor tyrosine kinase inhibitor: A network meta-analysis

Avash Das; Somnath Mahapatra; Dhrubajyoti Bandyopadhyay; Santanu Samanta; Sandipan Chakraborty; Lisa Liang Philpotts; Eiman Jahangir; Bhaskar Roy

doi:10.1016/j.critrevonc.2020.103186

Bleeding with vascular endothelial growth factor tyrosine kinase inhibitor: A network meta-analysis

Crit Rev Oncol Hematol. 2021 Jan:157:103186. doi: 10.1016/j.critrevonc.2020.103186. Epub 2020 Dec 9.

Authors

Avash Das¹, Somnath Mahapatra², Dhrubajyoti Bandyopadhyay³, Santanu Samanta⁴, Sandipan Chakraborty⁵, Lisa Liang Philpotts⁶, Eiman Jahangir⁷, Bhaskar Roy⁸

Affiliations

¹ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Avash.Das@UTSouthwestern.edu.
² Department of Pathology, University College of Medical Sciences, New Delhi, India.
³ Division of Internal Medicine, St. Luke Roosevelt Medical Center, Mount Sinai, NY, USA.
⁴ Department of Radiation Oncology, University of Maryland, MD, Baltimore, USA.
⁵ Department of Internal Medicine, Interfaith Medical Center, NY, USA.
⁶ Treadwell Library, Massachusetts General Hospital, Boston, MA, USA.
⁷ Divisions of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Department of Neurology, Division of Neuromuscular Medicine, Yale School of Medicine, New Haven, CT, USA. Electronic address: bhaskar.roy@yale.edu.

PMID: 33309571
DOI: 10.1016/j.critrevonc.2020.103186

Abstract

Background: Targeted therapies like vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are the first-choice treatment in several types of cancers. We aim to determine the comparative risk of bleeding events associated with the VEGFR-TKIs through a network meta-analysis.

Methods: Published data search up to November 2018 reporting bleeding in cancer patients treated with VEGFR-TKIs was performed. The primary outcome was presence of hemorrhagic events at the end of the trial. Bleeding as a side-effect profile was examined for eleven VEGFR-TKIs (Apatinib, Brivanib, Cabozantinib, Lenvatinib, Motesanib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib and Vandetanib). Network meta-analysis based on random effects model estimating Odds Ratio (OR) with 95 % confidence interval (CI), compared the risk of bleeding events among the VEGFR-TKIs with respect to placebo control conditions.

Results: Fifty Randomized Clinical Trials (RCTs) including 16,753 cancer patients were included in this analysis. Twenty studies compared VEGFR-TKIs with placebo, the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. VEGFR-TKIs were associated with increased incidence of all-grade hemorrhagic events in comparison to control (standard chemotherapy and/or placebo) (OR = 1.79; 95 % CI 1.50-2.13, p-value <0.0001) and placebo (OR = 1.50; 95 % CI 1.16-1.93, p-value = 0.1). However, there was no difference in high-grade bleeding in patients treated with VEGFR-TKI in comparison to control (OR = 1.22; 95 % CI 0.87-1.71, p-value 0.74) or placebo alone (OR = 1.05; 95 % CI 0.65-1.70, p-value 0.73). Among individual VEGFR-TKIs, Sunitinib (OR = 3.31, 95 % CI 2.34-4.69) and Regorafenib (OR = 2.92, 95 % CI 1.50-5.71) were associated with higher risk of hemorrhagic events in comparison to placebo.

Conclusion: VEGR-TKIs, particularly Sunitinib and Regorafenib appear to be associated with increased risk of bleeding incidence.

Trial registration number: PROSPERO CRD42017056406.

Keywords: Bleeding; Clinical trials systematic review/network meta-analysis; VEGFR-TKIs.

Publication types

Meta-Analysis
Review

MeSH terms

Angiogenesis Inhibitors
Humans
Network Meta-Analysis
Protein Kinase Inhibitors* / adverse effects
Receptors, Vascular Endothelial Growth Factor*
Vascular Endothelial Growth Factors

Substances

Angiogenesis Inhibitors
Protein Kinase Inhibitors
Vascular Endothelial Growth Factors
Receptors, Vascular Endothelial Growth Factor